Large Volume Visceral Fat Removal to Reverse Insulin Resistance in Type 2 Diabetes

大容量内脏脂肪切除术逆转 2 型糖尿病的胰岛素抵抗

• 批准号: 9344859
• 负责人: RAUL A BASTARRACHEA
• 金额: $ 29.69万
• 依托单位: MEDALITY MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344859
• 关键词: Accounting; Adipose tissue; Adult; Adverse effects; Affect; American; Animals; Area; Benchmarking; Blood Vessels; Body Composition; Body Weight decreased; Cataract; Cessation of life; Clinical Trials; Clinical assessments; Comorbidity; Connective Tissue; Data; Development; Disease; Dual-Energy X-Ray Absorptiometry; Esthetics; Euglycemic Clamping; Excision; Family suidae; Fatty acid glycerol esters; Female; Functional disorder; Glycosylated hemoglobin A; Goals; Gold; Health; Hemorrhage; Human; Individual; Insulin Resistance; Intervention; Italy; Kidney; Legal patent; Life Style; Link; Lipectomy; Liquid substance; Liver; Magnetic Resonance Imaging; Mechanics; Mesentery; Metabolic; Metabolism; Methods; Modeling; Modification; Morbidity - disease rate; Nerve; Nerve Tissue; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Omentum; Onset of illness; Operative Surgical Procedures; Outcome; Overweight; Pancreas; Papio; Phase Transition; Physiologic pulse; Plasma; Procedures; Recovery; Resolution; Retroperitoneal Space; Risk; Rodent; Saline; Secondary to; Skeletal Muscle; Solid; Stream; Structure; Suction Lipectomy; Techniques; Technology; Tissues; Vascularization; Viscera; Visceral; Weight Gain; Weight maintenance regimen; alternative treatment; base; diabetic patient; diet and exercise; disorder prevention; expectation; follow-up; improved; insulin sensitivity; male; phase II trial; pressure; subcutaneous; success

Abstract Excess visceral fat (VF) has been strongly linked with development of insulin resistance and subsequent type 2 diabetes (T2DM) in humans, and rodent lipectomy studies have demonstrated that this relationship is causal. Among the nearly 30 million US adults affected by T2DM, disease onset typically appears secondary to weight gain, with excess VF considered to be a major driver. Lifestyle changes (diet and exercise) are the first line of treatment for weight management and disease prevention, but such efforts have not proven effective over the long-term. Surgically removing subcutaneous fat by large volume liposuction has been explored as an alternative approach, but the vast majority of these studies have failed to consistently demonstrate improvement in metabolic outcomes. Therefore, targeting the VF depots for removal should be prioritized in order to rapidly and significantly improve metabolic and overall health in humans. However, due to the heavy vascularization and other delicate structures within and around VF, there are currently no feasible methods to perform this procedure. Studies targeting the omentum have been conducted with mixed results, likely because this depot only accounts for a fraction of total VF mass (~10%) in an obese human. Thus, additionally targeting the mesentery and peri- renal areas, where most VF is harbored, may be required to surgically treat T2DM. To this end, we have developed and commercialized a technology in use for removal of cataracts as well as subcutaneous fat depots, which we refer to as Tissue Liquefaction Technology™ (TLT). Our method is a unique, patented approach that delivers low levels of thermal and mechanical energy as a stream of warmed, low-pressurized, and pulsed saline, which causes susceptible non-connective tissues to undergo a phase transition from solid to liquid, while connective tissue-protected blood vessels and nerves are unharmed. Preliminary data demonstrate our ability to successfully target and remove these deep VF depots in pigs and baboons. Thus, the Specific Aim of this proposal is to determine feasibility and efficacy of large-volume VF removal in the baboon to reverse insulin resistance. This will be determined by surgically removing significant quantities of fat from all three VF depots (~75% of omentum, peri-renal, mesenteric fat) with TLT in 7 overweight and insulin resistant baboons, and determining effects on metabolic outcomes using `gold standard' techniques, including hyperinsulinemic- euglycemic clamps, DXA, MRI, MRS and a broad array of plasma metabolites at pre-determined intervals over 9 mo follow up. We have chosen to study insulin resistant baboons, since they are a well-validated model of human metabolism, and TLT has proven to easily and rapidly liquefy baboon (and human) VF in our preliminary studies. Our expectation is that animals will demonstrate exceptional recoveries, free of complications, have improved insulin sensitivity, without significant regrowth of VF depots or adverse effects on liver and skeletal muscle. In summary, our technology is a significant step forward for surgical fat removal, and if proven successful here, may represent a revolutionary treatment option for insulin resistance in T2DM and other conditions.

抽象的 过多的内脏脂肪 (VF) 与胰岛素抵抗和随后的 2 型胰岛素抵抗的发展密切相关 人类糖尿病（T2DM）和啮齿动物脂肪切除术研究表明这种关系是因果关系。 在近 3000 万受 T2DM 影响的美国成年人中，疾病的发作通常与体重有关 生活方式的改变（饮食和锻炼）是导致心室颤动增加的主要原因。 体重管理和疾病预防的治疗，但这些努力并没有被证明是有效的 长期来看，已探索通过大容量吸脂手术去除皮下脂肪作为替代方案。 方法，但绝大多数这些研究未能一致地证明在 因此，应优先考虑去除 VF 库，以便快速、有效地实现代谢结果。 改善人类的新陈代谢和显着的整体健康。 VF 内部和周围的其他精致结构，目前没有可行的方法来执行此程序。 针对网膜的研究结果好坏参半，可能是因为这个仓库只考虑了 对于肥胖人群中 VF 总质量的一小部分 (~10%) 因此，另外针对肠系膜和周围。 大多数 VF 所在的肾脏区域可能需要通过手术治疗 T2DM。 开发并商业化了一种用于去除白内障和皮下脂肪库的技术， 我们将其称为组织液化技术™ (TLT)。我们的方法是一种独特的专利方法。 低水平的热能和机械能，如加热、低压输送和脉冲盐水流， 这会导致敏感的非结缔组织经历从固体到液体的相变，同时 结缔组织保护的血管和神经没有受到伤害，初步数据证明了我们的能力。 成功地瞄准并去除猪和狒狒体内的这些深层 VF 库因此，这是该项目的具体目标。 提议是确定在狒狒身上进行大容量 VF 切除以逆转胰岛素的可行性和功效 这将通过手术从所有三个 VF 库中去除大量脂肪来确定。 （约 75% 的网膜、肾周、肠系膜脂肪）在 7 只超重和胰岛素抵抗狒狒中进行 TLT，以及 使用“金标准”技术确定对代谢结果的影响，包括高胰岛素血症 正常血糖钳夹、DXA、MRI、MRS 和一系列血浆代谢物，在预定的时间间隔内进行 我们选择研究胰岛素抵抗狒狒，因为它们是经过充分验证的模型。 人类新陈代谢，并且在我们的初步研究中，TLT 已被证明可以轻松快速地液化狒狒（和人类）VF 我们的研究期望动物能够表现出出色的恢复能力，没有并发症。 改善胰岛素敏感性，且 VF 库不会显着再生或对肝脏和骨骼产生不良影响 总之，如果证明成功的话，我们的技术是手术脂肪去除的重要一步。 在这里，可能代表了 T2DM 和其他疾病中胰岛素抵抗的革命性治疗选择。

项目成果

A Multicenter, Prospective, Randomized, Contralateral Study of Tissue Liquefaction Liposuction vs Suction-Assisted Liposuction.

组织液化吸脂术与抽吸辅助吸脂术的多中心、前瞻性、随机、对侧研究。

• 发表时间: 2018-08-16
• 影响因子: 2.9
• 作者: Hunstad, Joseph P;Godek, Christopher P;Van Natta, Bruce W;Kortesis, Bill G;Bharti, Gaurav;Crantford, John C;Daniels, Mark A;Andrew, Mark S
• 通讯作者: Andrew, Mark S